EP2695528A1 - Composition nutritionnelle pour améliorer la fonction musculaire et l'activité quotidienne - Google Patents

Composition nutritionnelle pour améliorer la fonction musculaire et l'activité quotidienne Download PDF

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Publication number
EP2695528A1
EP2695528A1 EP13191671.0A EP13191671A EP2695528A1 EP 2695528 A1 EP2695528 A1 EP 2695528A1 EP 13191671 A EP13191671 A EP 13191671A EP 2695528 A1 EP2695528 A1 EP 2695528A1
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Prior art keywords
combination
acid
nutritional composition
muscle
improving
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EP13191671.0A
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German (de)
English (en)
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EP2695528B1 (fr
Inventor
Klaske Van Norren
Adrianus Lambertus Bertholdus Van Helvoort
Joyce Faber
Robert Johan Joseph Hageman
Arjan Paul Vos
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Nutricia NV
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Nutricia NV
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Priority to PL13191671T priority Critical patent/PL2695528T3/pl
Priority to EP21179827.7A priority patent/EP3906788A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to a composition
  • a composition comprising proteinaceous matter that comprises leucine and an ⁇ -3 polyunsaturated fatty acid.
  • the invention also relates to the use of a composition suitable for improving the muscle function of a mammal.
  • the invention also relates to the use of a composition suitable for improving daily activity of a mammal.
  • Body composition, muscle functionality and daily activity are clinically highly relevant parameters, because muscle function and daily activity are important contributors to the quality of life of a cancer patient. Furthermore, an improved physical condition of a patient, as reflected in body composition and physical performance, might contribute to its compliance to an anti-cancer therapy. E.g. the dose of chemotherapy can be provided as scheduled, instead of being adjusted to a lower body weight of the patient.
  • Cachexia is one of the most debilitating aspects of cancer and has been associated with increased morbidity and mortality, with a reduced quality of life, an impaired response to chemotherapy, an increased susceptibility to chemotherapy-induced toxicity and higher incidence of postoperative complications.
  • Cancer cachexia can be defined as involuntary weight loss with a depletion of not only fat mass but also lean body mass due to muscle wasting. Symptoms besides mass loss are debilitation, weakness, edema, an impaired immune response and decline of motor and mental function. Cachectic patients have been shown to have higher resting energy expenditure which is not met by an increased nutrient intake, in many cases food intake is even reduced. Hence, approximately 45% of cancer patients loose more than 10% of their pre-diagnostic mass.
  • the tumor can induce metabolic changes in protein metabolism, resembling those found in infection or injury. These changes are characterized by net protein breakdown and increased oxidation of branched-chain amino acids (BCAAs) in muscle to support energy supply and synthesis of gluconeogenic amino acids.
  • BCAAs branched-chain amino acids
  • the breakdown of host protein is partly stimulated by inflammatory mediators produced by the host (e.g. TNF ⁇ , IL-6)(1), but also by the tumor, through the release of a proteolysis inducing factor (PIF)(4).
  • TNF ⁇ branched-chain amino acids
  • IL-6 branched-chain amino acids
  • PEF proteolysis inducing factor
  • BCAAs have also been supplemented in the presence of the tumor: patients undergoing chemotherapy received oral BCAA supplementation up to 1 year, resulting in a lower overall morbidity, improved nutritional status and better quality of life.
  • Other nutrients which may have anti-cachectic effects are ⁇ -3 polyunsaturated fatty acids (PUFAs).
  • PUFAs polyunsaturated fatty acids
  • the vast majority of the clinical trials in which ⁇ -3 PUFAs were tested report an increase or maintenance of body mass (BW); while in two clinical trials no effect on the loss of BW was found. In the latter, however, the supplementation period was only 2 weeks and/or included only a small number of patients.
  • Other effects of EPA or fish oil supplementation in cancer patients were a net lean tissue gain, an increase in total resting energy expenditure and physical activity level, a decrease in need for TPN and an improved quality of life, and even suggested improved survival.
  • WO 2004/026294 discloses nutritional compositions comprising a mixture of essential amino acids in free form and/or in salt form, rather than intact protein, for the promotion of muscle protein synthesis or controlling tumor-induced weight loss, such as cancer cachexia.
  • Intact protein may be present in addition.
  • a nutritional composition comprising at least 18 en% proteinaceous matter, at least part of which is whey protein, at least 12 wt. % leucine and an ⁇ -3 polyunsaturated fatty acid selected from the group of eicosapentaenoic acid, docosahexaenoic acid, eicosatetraenoic acid and docosapentaenoic acid is not described in a single combination.
  • Exemplified nutritional compositions comprise caseinate as protein source.
  • Example 2 of WO 2004/026294 it is concluded that ingestion of free essential amino acids is more effective than ingestion of a comparable amount of intact protein in stimulating net muscle protein synthesis.
  • EP 1 774 973 A1 discloses a composition comprising proteinaceous matter, said proteinaceous matter providing at least 24 en% and at least 12 wt% of leucine, based on total proteinaceous matter, for the treatment of insuline resistance. No compositions were exemplified.
  • a nutritional composition for such purpose.
  • the present invention relates to a combination of whey protein, leucine and at least one at least a ⁇ -3 polyunsaturated fatty acid selected from the group of eicosapentaenoic acid, docosahexaenoic acid, eicosatetraenoic acid and docosapentaenoic acid for improving the muscle function in a mammal.
  • the invention further relates to the a combination of whey protein, leucine and at least one at least a ⁇ -3 polyunsaturated fatty acid selected from the group of eicosapentaenoic acid, docosahexaenoic acid, eicosatetraenoic acid and docosapentaenoic acid for a use selected from the group of improving daily activity, improving physical performance, providing a better prognosis in terms of extended life-expectancy, improving compliance to an anti-cancer therapy and improving a quality of life.
  • This use may be in addition to improving the muscle function in a mammal or independent thereof.
  • Such a combination may in particular be in the form of a specific nutritional composition.
  • the present invention in particular relates to a nutritional composition, comprising
  • composition may be used for improving the muscle function in a mammal.
  • composition may in particular be used for a use selected from the group of improving daily activity, improving physical performance, providing a better prognosis in terms of extended life-expectancy, improving compliance to an anti-cancer therapy and improving a quality of life.
  • composition comprising whey protein (or in short: whey), leucine and at least one of said ⁇ -3 polyunsaturated fatty acids for a specific purpose - such as for improving the muscle function in a mammal - it is in particular meant these said components are intended to be used for that purpose in combination. Accordingly, each of said components is considered to play a role in accomplishing that purpose.
  • the energetic value of a compound (en%) is based on the energy provided by the digestible part (in particular in a human) of the compound.
  • the energetic value is based on the contribution of proteinaceous matter, lipids and digestible carbohydrates, using the following calculation factors: 4 kcal/g for digestible carbohydrates and proteinaceous matter and 9 kcal/g for lipids.
  • the organoleptic properties of the composition are such that the consumption is generally appreciated as pleasant.
  • the composition passes the stomach easily.
  • the digestible components of the composition become readily available upon intake of the product.
  • a composition according to the invention may in particular be used to improve skeletal muscle function in a mammal.
  • improving skeletal muscle function may comprise improving either one or both of muscle mass dependent and muscle mass independent loss of muscle function in a mammal.
  • muscle mass dependent muscle function loss it may comprise a correction in maximal force, maximal contraction velocity or maximal relaxation velocity of skeletal muscle.
  • muscle mass independent loss of muscle function it may comprise a correction in maximal force corrected for muscle mass, maximal contraction velocity corrected for muscle mass or maximal relaxation velocity corrected for muscle mass.
  • the time needed for a contraction or relaxation might be improved.
  • composition of the invention may be used to prevent or treat a reduction of muscle function due to, or resulting from aging, disease, disorder, drugs or trauma, preferably drug, disease or disorder.
  • Reduced muscle function may in particular manifest itself as a symptom due to a disease or disorder such as cancer, HIV infection, COPD, renal failure, heart failure, and a disease state characterized by a high plasma and/or serum level of pro-inflammatory cytokines.
  • a disease or disorder such as cancer, HIV infection, COPD, renal failure, heart failure, and a disease state characterized by a high plasma and/or serum level of pro-inflammatory cytokines.
  • the composition of the invention may in particular be used for treating a mammal suffering from a disease or disorder selected from the group of cancer, HIV infection, COPD, renal failure, heart failure, and a disease state characterized by a high plasma and/or serum level of pro-inflammatory cytokines.
  • the disease or disorder is a cancer.
  • the reduced muscle function may be a muscle mass dependent function loss or a muscle mass independent function loss.
  • the invention relates also to a nutritional composition according to the invention, wherein the drug is administered in the framework of a chemotherapy.
  • compositions according to the invention are fed to tumour-bearing mice, as illustrated in the example below, it is contemplated by the inventors that a composition of the invention is effective in improving the muscle function of a mammal. It was shown in the experiments that at least one of several physiological parameters associated with a reduced muscle function was positively affected.
  • composition of the invention may be used to provide a better prognosis in terms of extended life-expectancy and/or a better quality of life.
  • Factors improving the quality of life are in particular less fatigue, improved daily activity, more stamina, improved contrast between day time and night time activity (nocturnal sleep), better general condition and less periods of feeling depressed.
  • Proteinaceous matter is formed by moieties formed from amino acids.
  • amino acids as used herein includes amino-acid residues (e.g. in peptides).
  • the term 'proteinaceous matter' includes free amino acids, amino acid salts, amino acid esters, the amino acid residues bound to conjugating molecules and peptides, including proteins.
  • a specific amino acid e.g. leucine
  • this is meant to include the specific amino acid (residues) present as a salt, in a bound form, as well as the free specific amino acid.
  • a peptide is meant a combination of two or more amino acids, connected via one or more peptidic bonds.
  • amino acids are named amino-acid residues.
  • Peptides include oligopeptides and polypeptides, including proteins.
  • polypeptide a peptide chain comprising 14 or more amino-acid residues.
  • oligopeptide a peptide chain comprising 2 to 13 amino-acid residues.
  • Chiral amino acids present in a composition of the invention may be in the L-form or the D-form. Usually, the chiral amino acids present in a composition of the invention are in the L-form.
  • a liquid composition according to the invention comprises at least 7 g/100 ml of proteinaceous matter, preferably at least 8 g/100 ml, more preferably at least 9 g/100 ml, most preferably at least 10 g/100 ml.
  • the proteinaceous matter in a composition of the invention provides at least 18 en%, preferably at least 20 en%, more preferably at least 22 en% of the total composition.
  • the proteinaceous matter in a composition of the invention usually provides 60 en% or less, preferably 40 en% or less, or more preferably 32 en% or less of the total composition.
  • the proteinaceous matter comprises whey protein.
  • Whey protein is in inter alia considered advantageous, because it has a fast post-prandial release of amino acids into blood, compared to e.g. casein.
  • the threshold concentration of amino acids needed to switch on the anabolic signal of muscle protein synthesis can be reached easier ( e.g. at a lower dosage of proteinaceous matter, or sooner after ingestion).
  • the proteinaceous matter may further comprises proteinaceous matter from one or more other protein sources, in particular one or more proteinaceous matter sources selected from the group of casein, caseinate, soy and wheat, preferably casein.
  • Said protein source or part thereof may have been modified, in particular by (partial) hydrolysis.
  • whey is meant a source of a globular protein that can be isolated from whey.
  • globular whey proteins can be selected from beta-lactoglobulin, alpha-lactalbumin and serum albumin, including mixtures thereof.
  • mixtures that contain whey proteins are whey isolate and whey concentrate. Both sources contain predominantly intact whey proteins, which is preferred in the contect of this application.
  • the proteinaceous matter comprises at least 10 wt%, preferably at least 15 wt%, more preferably at least 20 wt%, most preferably at least 25 wt% of whey, based on the total proteinaceous matter.
  • the whey fraction is 50 wt. % or less based on total proteinaceous matter, in particular 40 wt% or less based on total proteinaceous matter, although - if desired - more than 50 wt. % to 100 % of the proteinaceous matter may be provided by whey.
  • the concentration of denaturated whey preferably does not exceed 35 wt% based on total proteinaceous matter. This is advantageous with respect to avoiding the risk of gelation during storage. Also, the choice of whey over free amino acids is preferred as free amino acids have a bad taste.
  • the presence of whey may offer a number of advantages.
  • the whey shows an advantageous release behaviour both in terms of release rate of the amino acids and the tendency to make the amino acids available for uptake by the body, essentially at the same time.
  • the advantageous amino-acid release behaviour may be further enhanced by (slightly) hydrolysing at least part of the whey protein, usually to the extent that up to 20 % of the protein is hydrolysed to free amino acids, preferably to the extent that up to 10 % of the protein is hydrolysed to free amino acids.
  • whey protein or less is (slightly) hydrolysed, in particular 10 to 50 wt%.
  • the free amino acid or part thereof may be removed from the hydrolysate. Suitable techniques are known, e.g. filtration, chromatography or absorption.
  • whey protein(s) preferably a whey fraction is chosen comprising less that 20 wt% casein glycomacropeptide (GMP), more preferably less than 10 wt%.
  • GMP casein glycomacropeptide
  • the beta-lactoglobulin content preferably is larger than 40 wt%, more preferably 46 to 80 wt%.
  • the casein When used as intact protein, the casein preferably comprises a high concentration of beta casein, in particular more than 36 g/100 g casein, more in particular 38 to 70 g/100 g casein.
  • the proteinaceous matter is present in the form of free amino acids, a salt thereof or as a conjugate with a conjugating molecule other than a protein or peptide, which conjugate is capable of being split in the free amino acid (or salt thereof) and the conjugating compound under the influence of a bile constituent and/or a pancreas excretes in duodenum and/or the ileum.
  • the amount of amino acid in such form is up to 15 wt% based on total proteinaceous matter, preferably 0.5-14 wt%.
  • the peptide content (oligopeptide, polypeptide, protein) based on total proteinaceous matter is usually at least 50 wt%, at least 60 wt% or at least 75 wt%.
  • the wt% of peptide based on total proteinaceous matter is usually up to 99 wt%, preferably up to 94 wt%, more preferably 89 wt%.
  • An advantage of a composition wherein the peptide content is high is that the taste, or another organoleptic property of the composition, usually is appreciated better when consumed (orally). Further, the uptake of amino acids by the body may be more gradual.
  • the composition comprises leucine in the form of a free acid, a salt, a dipeptide or a conjugate with a conjugating compound other than an amino acid, a protein, or a peptide, which conjugate is capable of being split into the free amino acid (or salt thereof), preferably in the gut or stomach or after absorption in the enterocytes or liver.
  • Leucine is preferably for at least 35 wt%, more preferably for at least 40 wt%, based on the total proteinaceous leucine, present in the form of a peptide (oligopeptide, polypeptide, protein), preferably in the form of polypeptides and/or (intact) proteins.
  • Leucine is for up to 100 wt%, preferably for up to 80 wt%, based on the total proteinaceous leucine, present in the form of a peptide (oligopeptide, polypeptide, protein), more preferably in the form of one or more polypeptides and/or one or more (intact) proteins.
  • the leucine content in a composition of the invention is at least 12 wt%, at least 13 wt%, at least 16 wt% or at least 19 wt%, based on total proteinaceous matter.
  • the leucine content is 50 wt% or less, In particular, it may be 30 wt% or less, 25 wt% or less or 23 wt% or less, based on total proteinaceous matter.
  • the leucine content is 12 to 23 wt%, based on total proteinaceous matter.
  • composition may comprise glutamine and/or glutamic acid.
  • the glutamine content (determined as total glutamine & glutamic acid) is at least 15 wt%, based on total proteinaceous matter. In an embodiment, the glutamine content is 16 to 28 wt%, preferably 17 to 26 wt%, based on total proteinaceous matter.
  • the composition may comprise one or more of the group of cystine, cysteine and cysteine equivalents such as N-acetyl cysteine. preferably in an amount of at least 0.8 wt%, based on total proteinaceous matter.
  • the content of cystine, cysteine and cysteine equivalents is 11 wt% or less, In particular, it is 8 wt% or less, based on total proteinaceous matter. In an embodiment, the content of cystine, cysteine and cysteine equivalents is 0.8 to 8 wt%, based on total proteinaceous matter.
  • Glutathione homeostasis plays a role in maintaining whole body resistance to oxidative stress. Severe oxidative stress in the muscle might lead to decreased muscle function.
  • the inventors found that glutathione levels of the liver were significantly decreased. The liver is the main distributor of glutathione and therefore liver glutathione is a good reflection of whole body glutathione.
  • further experiments by the inventors revealed that at least partial normalization of the glutathione level in liver cells occurred under the influence of glutamine and/or cysteine in a composition of the invention. Particularly good results were obtained when both amino acids were present in the composition.
  • composition of the invention comprising glutamine or cysteine, preferably in a concentration as indicated above, is particularly effective in improving the muscle function of a mammal. It is further contemplated that the presence of both glutamine and cysteine in a composition of the invention is even more effective in improving the muscle function of a mammal.
  • an advantageous effect of glutamine and/or cysteine on the muscle function of a mammal is obtained with a composition of the invention comprising whey protein and casein.
  • the weight ratio leucine/ (valine+isoleucine) is generally 1.0 or more, preferably 1.05 or more.
  • the content of essential amino acids usually is at least 49 wt%, preferably 49 to 80 wt%, more preferably 52 to 70 wt% of the total proteinaceous matter is formed by essential amino acids.
  • the lysine content usually is 7 to 15 g/100g of proteinaceous matter, preferably 7.5 to 14 g/100 g of proteinaceous matter.
  • Decreasing muscle protein breakdown with the composition of the invention may also help reduce carnitine and/or lysine loss from catabolic muscle and help maintain muscle carnitine and lysine levels.
  • the composition of the invention comprising carnitine might aid to skeletal muscle function.
  • L-carnitine (beta-acetoxy-gamma-N, N, N-trimethylaminobutyrate) is synthesized from the essential aminoacids lysine and methionine mainly in liver and kidney. Carnitine is required for the transport of medium/long-chain fatty acids across mitochondrial membranes, which then can enter beta-oxidation.
  • Carnitine deficiency has been reported in several forms of cancer and has been associated with increased fatigue. Three open labels studies indeed suggest that treatment with carnitine reduced fatigue, measured with a fatigue score. Especially one derivative of carnitine, acid-soluble acyl-carnitine seems to be decreased in cancer patients compared to healthy controls. For total carnitine, a significant decrease has been reported after three months of therapy and seems to suggest that carnitine deficiency is induced by chemotherapy. Another explanation for the onset of a carnitine deficiency may be that the decrease in carnitine levels is associated with the presence of cachexia. In conclusion, carnitine deficiency seems to be induced by both chemotherapy and progression of disease (cachexia). These findings suggest that supplementation with a composition of the invention comprising carnitine may best start immediately after diagnosis in order to prevent a deficiency.
  • the carnitine content in a composition of the invention is usually at least 5 mg per 100 kcal, preferably at least 10 mg per 100 kcal, at least 25 mg per 100 kcal or at least 100 mg per 100 kcal.
  • the carnitine content is 2.5 g or less per 100 kcal, in particular 1.25 g or less per 100 kcal.
  • the carnitine content is preferably at least 10 mg/100 ml, at least 50 mg/100 ml or at least 200 mg/100 ml.
  • the carnitine content is 5 g or less per 100 ml, in particular 2.5 g or less per 100 ml.
  • Taurine is the most abundant free amino acid in cardiac and skeletal muscle and with decrease of muscle mass it is excreted from the muscle. Taurine is thought to play an important role in ion movement and calcium handling of the muscle and might therefore influence muscle performance. Taurine depletion causes cardiomyocyte atrophy, mitochondrial and myofiber damage and cardiac dysfunction, effects likely related to the actions of taurine. Decreasing muscle protein breakdown using a composition of the invention may also help reduce taurine loss from catabolic muscle and help maintain muscle taurine levels and in this way maintain muscle function.
  • the taurine content in a composition of the invention is usually at least 5 mg per 100 kcal, preferably at least 10 mg per 100 kcal, at least 25 mg per 100 kcal or at least 100 mg per 100 kcal.
  • the taurine content is 2.5 g or less per 100 kcal, in particular 1.25 g or less per 100 kcal.
  • the taurine content is preferably at least 10 mg/100 ml, at least 50 mg/100 ml or at least 200 mg/100 ml.
  • the taurine content is 5 g or less per 100 ml, in particular 2.5 g or less per 100 ml.
  • the lipid fraction in a composition of the invention, usually provides at least 10 en%, preferably at least 20 en% or more preferably at least 25 en% of the total composition.
  • the lipid fraction in a composition of the invention usually provides 50 en% or less, preferably 40 en% or less, or more preferably 35 en% or less of the total composition.
  • lipid fraction' is meant a fraction comprising one or more lipids, including fatty acids, fatty-acid derivatives (including tri-, di-, and monoglycerides and phospholipids) and sterol-containing metabolites such as cholesterol.
  • a composition of the invention comprises at least one ⁇ -3 polyunsaturated fatty acid selected from the group of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), eicosatetraenoic acid (ETA) and docosapentaenoic acid (DPA).
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • ETA eicosatetraenoic acid
  • DPA docosapentaenoic acid
  • a composition of the invention may further comprise ⁇ -3 and/or ⁇ -6 polyunsaturated fatty acids, in particular those containing 18 to 26 carbon atoms, e.g. linolenic acid (LA), alpha linolenic acid (ALA), gamma linolenic acid (GLA), dihomo gamma-linolenic acid (DGLA) and arachidonic acid (AA).
  • LA linolenic acid
  • ALA alpha linolenic acid
  • GLA gamma linolenic acid
  • DGLA dihomo gamma-linolenic acid
  • AA arachidonic acid
  • the ⁇ -3 unsaturated fatty acid content is usually at least 10 wt%, preferably at least 15 wt%, based on total lipid content.
  • the composition of the invention comprises stearidonic acid (SDA).
  • SDA stearidonic acid
  • Nutritional oils containing SDA are reported to be a dietary source of ⁇ -3 fatty acids that would be more effective in increasing tissue EPA and DPA concentrations than are current ALA-containing oils.
  • the lipid fraction in the composition comprises more than 0.5 wt% of SDA, more preferable more than 0.6 wt% of SDA, still more preferably more than 1.2 wt% of SDA, based on total lipid.
  • the maximum amount is more or less limited by the particular source used (type of marine oil), but marine oils with an SDA amount of 2 wt% to about 5 wt% (based on total lipid in the latter oil) are commercially available.
  • the amount of SDA in the lipid fraction ranges between 0.5 and 5 wt%, based on total lipid. It is preferred that the amount of SDA is relatively high compared to that of docosahexaenoic acid (DHA) and/ or linoleic acid (LA). This allows a high efficacy and manufacture of palatable products comprising low amounts of oxidized products.
  • the weight ratio of SDA to DHA is therefore at least 0.22, preferably at least 0.25, more preferably at least 0.30.
  • a composition of the invention may in particular be a composition wherein at least 55 wt% of the lipid fraction, preferably triglyceride oils, comprise at least 4 wt% of one or more of eicosapentaenoic acid and docosahexaenoic acid.
  • the lipid fraction comprises less than 30 wt% of a saturated fatty acid, preferably less than 22 wt%, based on total lipid content.
  • the ratio ⁇ -3 to ⁇ -6 polyunsaturated fatty acids can be chosen within wide limits, e.g. from 0.2 to 10, or from 0.4 to 3.0.
  • the ratio ⁇ -3 to ⁇ -6 polyunsaturated fatty acids is less than 1.0, preferably 0.97 or less, more preferably 0.95 or less.
  • the ratio is preferably larger 0.5 or more, more preferably 0.6 or more.
  • the ratio is from 0.5 to 0.97, more preferably from 0.6 to 0.95.
  • a composition of the invention comprises a digestible carbohydrate fraction, providing at least 20 en%, preferably at least 30 en% or more preferably at least 38 en% of the total composition.
  • the digestible carbohydrate fraction in a composition of the invention usually provides 70 en% or less, preferably 60 en% or less, more preferably 48 en% of the total composition.
  • 'digestible carbohydrate' fraction is meant a fraction comprising one or more digestible carbohydrates.
  • Digestible carbohydrates include maltodextrose, maltose and glucose.
  • a carbohydrate is considered digestible in case more than 90 % of quickly carbohydrates are digested within 20 min in accordance with the Enquist method.
  • composition of the carbohydrate fraction may be chosen to achieve a favourable carbohydrate uptake, and accordingly a desirable insulin release after intake. Accordingly, in particular a composition meeting one or more of the following criteria with respect to the carbohydrate content are considered to be advantageous.
  • less than 75 wt% of the carbohydrates is formed by the sum of the sucrose and the maltodextrin content.
  • At least 40 wt% based on the total weight of the carbohydrates is formed by slowly digestible carbohydrates, i.e. in particular carbohydrates which are digested less fast than maltodextrose, maltose and glucose
  • a composition according to the invention comprises less than 60 wt%, preferably 20 to 50 wt% based on the total weight of the carbohydrates of quickly digestible carbohydrates, in particular of maltodextrose, maltose, glucose and other carbohydrates which are digested at least as fast.
  • more than 20 wt% based on the total weight of the carbohydrates is formed by at least one disaccharide, preferably 22 to 60 wt%.
  • the disaccharide is preferably selected from the group consisting of sucrose, trehalose, palatinose, lactose and other low glycemic disaccharides, more preferably from trehalose and palatinose.
  • At least one monosaccharide other than glucose is present.
  • said monosaccharide is selected from the group consisting of galactose, mannose and ribose.
  • the total amount of said monosaccharide(s) is 0.5 to 30 wt%, more preferably 5 to 25 wt% based on the total weight of the carbohydrates.
  • the presence of ribose is advantageous, preferably in combination with (endogenous) folic acid, to increase the protein synthesis. It is contemplated that the combination of these two compounds allows an increase in the production of guanosine triphosphate in the mammal, resulting in an increase of the protein synthesis via stimulation of eukaryotic initiation factor 2B, especially in malnourished patients.
  • the folic acid may be provided in one or more of the following forms: free folic acid, folinic acid, formylated folic acid, methylated folic acid, preferably in a reduced form or as a mono- or polyglutamate conjugated derivative. When present, the folic acid content is usually at least 95 ⁇ g per 100 kcal carbohydrates, preferably 110 to 400 ⁇ g per 100 kcal carbohydrates, more preferably 125 to 300 ⁇ g per 100 kcal carbohydrates.
  • the composition has a relatively low glycemic index.
  • a combination or composition according to the invention to having a low glycemic index is advantageous with respect to muscle protein synthesis, and/or muscle strength, because it contributes to a high insulin sensitivity of the muscle.
  • a high insulin sensitivity is considered to be beneficial in that it improves the stimulating effect of insulin on muscle synthesis (insulin stimulation being a trigger for switching on the anabolic signal of muscle).
  • the composition is a nutritional composition with a low glycemic index.
  • the glycemic index of the composition is below 55, preferably below 45.
  • the glycemic index will be above zero, and usually be at least 1, in particular at least 5. Details on how to determine the glycemic index of a composition are provided in the Examples, herein below.
  • the skilled person will be able to formulate a composition with a relatively low glycemic index based on the information disclosed herein and common general knowledge.
  • the glycemic index of a composition is decreased.
  • Preferred examples of carbohydrates which are digested more slowly than glucose are isomaltulose, fructose, galactose, lactose, trehalose.
  • carbohydrates which are digested more slowly than glucose are isomaltulose, fructose, galactose, lactose, trehalose.
  • sugar and fibre can slow down gastric emptying.
  • fibres can form a physical barrier in the intestine, reducing absorption rate.
  • Amino acids from protein can increase insulin release (especially leucine), and thereby increase glucose uptake by the cells. All these mechanisms can contribute to a reduction in glycemic index.
  • composition of the invention comprises an indigestible carbohydrate fraction
  • the indigestible carbohydrate is selected from the group of galactooligosaccharides and fructooligosaccharides.
  • the galactooligosaccharide is selected from the group of short-chain galactooligosaccharides, long-chain galactooligosaccharides, or any combination thereof.
  • the fructooligosaccharide is selected from the group of short-chain fructooligosaccharides, long-chain fructooligosaccharides, or any combination thereof.
  • a preferred composition comprises a galactooligosaccharide and a fructooligosaccharide.
  • the molar ratio of galactooligosaccharide to fructooligosaccharide ranges from 1:1 to 20:1, preferably from 5:1 to 12:1, and is most preferably equal to about 9:1.
  • oligosaccharide a chain comprising 2 to 25 saccharide residues.
  • oligosaccharide chain comprising 10-25 saccharide residues.
  • oligosaccharide chain comprising 2-9 saccharide residues, for example 2-5 residues or 6-9 residues.
  • Indigestible carbohydrates are carbohydrates that remain in essence undigested in the human intestines.
  • a carbohydrate is considered indigestible in case less than 10 % of the sugars is released within 20 and 120 min in an analysis setting using standard digestive enzymes, as determinable by the Enquist method.
  • the indigestible carbohydrate is selected from the group of galactomannans having a degree of polymerisation (DP) between 2 and 50, xylans with a DP of 2 to 60, oligomers having more than 30 wt% of galacturonic acid or glucuronic acid moieties having a molecular weight of 520 to 2200 Dalton, and any combination thereof.
  • DP degree of polymerisation
  • the indigestible carbohydrate content is at least 1 wt%, at least 2 wt% or at least 3 wt%, based on total dry matter. In an embodiment, the indigestible carbohydrate content amounts 1 to 15 wt%, preferably 2 to 12 wt%, more preferably 3 to 10 wt%, based on total dry matter.
  • the composition according to the invention may comprise a mixture of neutral and acid oligosaccharides as disclosed in WO 2005/039597 (N.V. Nutricia ), which is incorporated herein by reference in its entirety.
  • the acid oligosaccharide has a degree of polymerization (DP) between 2 and 5000, preferably between 2 and 1000, more preferably between 2 and 250, even more preferably between 2 and 50, most preferably between 2 and 10. If a mixture of acid oligosaccharides with different degrees of polymerization is used, the average DP of the acid oligosaccharide mixture is preferably between 2 and 1000, more preferably between 3 and 250, even more preferably between 3 and 50.
  • the acid oligosaccharide may be a homogeneous or heterogeneous carbohydrate.
  • the acid oligosaccharides may be prepared from pectin, pectate, alginate, chondroitine, hyaluronic acids, heparin, heparane, bacterial carbohydrates, sialoglycans, fucoidan, fucooligosaccharides or carrageenan, and are preferably prepared from pectin or alginate.
  • the acid oligosaccharides may be prepared by the methods described in WO 01/60378 , which is hereby incorporated by reference.
  • the acid oligosaccharide is preferably prepared from high methoxylated pectin, which is characterized by a degree of methoxylation above 50%.
  • degree of methoxylation also referred to as DE or “degree of esterification”
  • the acid oligosaccharides are preferably characterized by a degree of methoxylation above 20%, preferably above 50 % even more preferably above 70%.
  • the acid oligosaccharides have a degree of methylation above 20%, preferably above 50 % even more preferably above 70%.
  • the acid oligosaccharide is preferably administered in an amount of between 10 mg and 100 gram per day, preferably between 100 mg and 50 grams per day, even more between 0.5 and 20 gram per day.
  • neutral oligosaccharides refers to saccharides which have a degree of polymerization of monose units exceeding 2, more preferably exceeding 3, even more preferably exceeding 4, most preferably exceeding 10, which are not or only partially digested in the intestine by the action of acids or digestive enzymes present in the human upper digestive tract (small intestine and stomach) but which are fermented by the human intestinal flora and preferably lack acidic groups.
  • the neutral oligosaccharide is structurally (chemically) different from the acid oligosaccharide.
  • neutral oligosaccharides as used in the present invention preferably refers to saccharides which have a degree of polymerization of the oligosaccharide below 60 monose units, preferably below 40, even more preferably below 20, most preferably below 10.
  • monose units refers to units having a closed ring structure, preferably hexose, e.g. the pyranose or furanose forms.
  • the neutral oligosaccharide preferably comprises at least 90%, more preferably at least 95% monose units selected from the group consisting of mannose, arabinose, fructose, fucose, rhamnose, galactose, ⁇ -D-galactopyranose, ribose, glucose, xylose and derivatives thereof, calculated on the total number of monose units contained therein.
  • Suitable neutral oligosaccharides are preferably fermented by the gut flora.
  • the oligosaccharide is selected from the group consisting of: cellobiose (4-O- ⁇ -D-glucopyranosyl-D-glucose), cellodextrins ((4-O- ⁇ -D-glucopyranosyl) n -D-glucose), B-cyclodextrins (Cyclic molecules of ⁇ -1-4-linked D-glucose; ⁇ -cyclodextrin-hexamer, ⁇ -cyclodextrin-heptamer and ⁇ -cyclodextrin-octamer), indigestible dextrin , gentiooligosaccharides (mixture of ⁇ -1-6 linked glucose residues, some 1-4 linkages), glucooligosaccharides (mixture of ⁇ -D-glucose), isomaltooligosaccharides (linear ⁇ -1-6 linked glucose residues with some 1-4 linkages), isomaltose
  • the neutral oligosaccharide is selected from the group consisting of fructans, fructooligosaccharides, indigestible dextrins galactooligosaccharides (including transgalactooligosaccharides), xylooligosaccharides, arabinooligosaccharides, glucooligosaccharides, mannooligosaccharides, fucooligosaccharides and mixtures thereof.
  • the neutral oligosaccharide is selected from the group consisting of fructooligosacchararides, galactooligosaccharides and transgalactooligosaccharides.
  • Suitable oligosaccharides and their production methods are further described in Laere K.J.M. ( Laere, K.J.M., Degradation of structurally different non-digestible oligosaccharides by intestinal bacteria: glycosylhydrolases of Bi. adolescentis. PhD-thesis (2000), Wageningen Agricultural University, Wageningen, The Netherlands ), the entire content of which is hereby incorporated by reference.
  • Transgalactooligosaccharides are for example sold under the trademark VivinalTM (Borculo Domo Ingredients, Netherlands).
  • Indigestible dextrin which may be produced by pyrolysis of corn starch, comprises ⁇ (1 ⁇ 4) and ⁇ (1 ⁇ 6) glucosidic bonds, as are present in the native starch, and contains 1 ⁇ 2 and 1 ⁇ 3 linkages and levoglucosan. Due to these structural characteristics, indigestible dextrin contains well-developed, branched particles that are partially hydrolysed by human digestive enzymes. Numerous other commercial sources of indigestible oligosaccharides are readily available and known to skilled person. For example, transgalactooligosaccharide is available from Yakult Honsha Co., Tokyo, Japan. Soybean oligosaccharide is available from Calpis Corporation distributed by Ajinomoto U.S.A. Inc., Teaneck, N.J.
  • the composition according to the invention comprises an acid oligosaccharide with a DP between 2 and 250, prepared from pectin, alginate, and mixtures thereof ; and a neutral oligosaccharide, selected from the group of fructans, fructooligosaccharides, indigestible dextrins, galactooligosaccharides including transgalactooligosaccharides, xylooligosaccharides, arabinooligosaccharides, glucooligosaccharides, mannooligosaccharides, fucooligosaccharides, and mixtures thereof.
  • a neutral oligosaccharide selected from the group of fructans, fructooligosaccharides, indigestible dextrins, galactooligosaccharides including transgalactooligosaccharides, xylooligosaccharides, arabinooligosaccharides, glucooligosaccharides, manno
  • composition according to the invention comprises two chemically distinct neutral oligosaccharides. It was found that the administration of acid oligosaccharides combined with two chemically distinct neutral oligosaccharides provides an optimal synergistic immune stimulatory effect.
  • composition according to the invention comprises:
  • a mixture of acid- and neutral oligosaccharides is preferably administered in an amount of between 10 mg and 100 gram per day, preferably between 100 mg and 25 grams per day, even more preferably between 0.5 and 20 gram per day.
  • a nutritional composition is meant a composition that comprises naturally occurring components, preferably found in the food supply, that can be sold over the counter, as supplements, functional foods or food ingredients i.e. without a physician's or veterinarian's prescription.
  • a nutritional composition may also be a medical food, intended for the dietary management of a disease or condition for mammals under the supervision of a physician or veterinarian.
  • a composition according to the invention may be in the form of a liquid, e.g. a drink, in the form of a semi-liquid, e.g. a yoghurt or a custard, in the form of a gel, e.g. jelly cake or in the form of a solid, e.g. a candy bar or an ice-cream.
  • a liquid e.g. a drink
  • a semi-liquid e.g. a yoghurt or a custard
  • a gel e.g. jelly cake
  • a solid e.g. a candy bar or an ice-cream.
  • a liquid composition is prepared from a concentrate, e.g. from a liquid (e.g. with a viscosity of less than about 80 mPa.s), a semi-liquid (e.g. with a viscosity of more than about 80 mPa.s and less than about 400 mPa.s), a gel or a solid.
  • a concentrate e.g. from a liquid (e.g. with a viscosity of less than about 80 mPa.s), a semi-liquid (e.g. with a viscosity of more than about 80 mPa.s and less than about 400 mPa.s), a gel or a solid.
  • water may be used to dilute the concentrate.
  • such preparation occurs just before administration of the composition, e.g. in an instant-fashion.
  • One particular embodiment of the invention is a nutritional composition
  • a nutritional composition comprising proteinaceous matter, a lipid, and a digestible carbohydrate, wherein
  • the total energetic value of a liquid composition in accordance with the invention may be chosen within wide limits, e.g. from 0.2 to 4 kcal/ml. Usually it is at least 0.3 kcal/ml, in particular at least 0.8 kcal/ml, more in particular at least 1.2 kcal/ml. Usually, it is 3.0 kcal/ml or less, in particular 2.6 kcal/ml or less, more in particular 2.4 kcal/ml or less. In a specific embodiment, the liquid composition in accordance with the invention has an energetic value in the range of 0.3 to 3.0 kcal/ml, preferably 0.8 to 2.6 kcal/ml, more preferably 1.2 to 2.4 kcal/ml.
  • the liquid composition in accordance with the invention has an energetic value in the range of 0.2 to 1.0 kcal/ml, preferably 0.4 to 0.9 kcal/ml.
  • Factors that play a role in determining a desirable energetic value include the ease of achieving a higher en% proteinaceous matter on the one hand and a fast emptying of the stomach (increasing anabolic response) on the other hand.
  • the total energetic value of a semi-liquid, gel or solid composition in accordance with the invention may be chosen within wide limits, e.g. from 1 to 15 kcal/g. Usually, it is at least 2.0 kcal/g, preferably at least 2.8 kcal/g, even more preferably at least 3.2 kcal/g. Usually, it is 12 kcal/g or less, preferably 10 kcal/g or less, even more preferably 8.0 kcal/g or less. In a specific embodiment, the semi-liquid, gel or solid composition in accordance with the invention has an energetic value in the range of 3.2 to 8.0 kcal/g.
  • the composition may comprise one or more other additional components such as at least one component selected from the group consisting of minerals, trace elements and vitamins, preferably selected from the group consisting of sodium, potassium, chloride, fluoride, iodide, calcium, phosphorous, magnesium, vitamin A, vitamin D3, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, folic acid, vitamin B12, biotin, vitamin C, lipoic acid, zinc, iron, copper, manganese, molybdenum selenium and chromium.
  • vitamins preferably selected from the group consisting of sodium, potassium, chloride, fluoride, iodide, calcium, phosphorous, magnesium, vitamin A, vitamin D3, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, folic acid, vitamin B12, biotin, vitamin C, lipoic acid, zinc, iron, copper, manganese, molybdenum selenium and chromium.
  • Such components may be present in a concentration up to the daily recommended dose per daily serving.
  • Zinc is preferably present in a concentration of at least 2.8 mg per 100 kcal carbohydrates, more preferably of 5.6 to 20 mg per 100 kcal carbohydrates, even more preferably of 6-15 mg per 100 kcal carbohydrates.
  • the composition in accordance with the invention further comprises a sustained release preparation effective to release an amino acid in the duodenum and/or the ileum, said preparation comprising at least one component selected from the group consisting of amino acids in the form of a free acid, amino acids in the form of a salt and amino acids in the form of a conjugate with a conjugating compound other than a protein which conjugate is capable of being split in the free amino acid (or salt thereof) and the conjugating compound under the influence of a bile constituent and/or a pancreas excrements in duodenum and/or the ileum.
  • a sustained release preparation effective to release an amino acid in the duodenum and/or the ileum
  • said preparation comprising at least one component selected from the group consisting of amino acids in the form of a free acid, amino acids in the form of a salt and amino acids in the form of a conjugate with a conjugating compound other than a protein which conjugate is capable of being split in the free amino acid (or salt thereof) and
  • the amino acid in the sustained release form is preferably suspended in a liquid, semi- liquid or solid product.
  • the sustained release preparation can be made based upon conventional techniques.
  • the amino acid(s) may be coated with a pH sensitive material that dissolves at the pH existing in the duodenum/ileum (about pH 7) but not in the stomach (strongly acidic). Such coatings are generally known in the art.
  • conjugating molecules are molecules forming specific peptides with the amino acid that are not split by pepsin, or at least not efficiently split under physiological conditions. Examples are choline, betain, dimethylglycine and sarcosine. Other suitable conjugating molecules include phospholipids, lyso-phospholipids and glycerol.
  • Amino acids that are preferably present in the sustained release preparation are preferably selected from leucine and other essential amino acids, in particular methionine, arginine, tryptophan, phenylalanine and lysine, of which leucine is especially preferred.
  • a composition according to the invention is administered in a drug regimen.
  • the composition can be used as adjuvant of a drug, such as a drug selected from the group consisting of anti-cancer drugs, anti-retroviral drugs, antihypertensives, anti-thrombotics, anti-depressants and anti-diabetic drugs.
  • a drug selected from the group consisting of anti-cancer drugs, anti-retroviral drugs, antihypertensives, anti-thrombotics, anti-depressants and anti-diabetic drugs.
  • metformin or another anti-diabetic drug are considered to be stable in a composition according the invention and to be very effective.
  • Said drug may be present in the composition according to the invention or be administered separately.
  • the invention further relates to a method for improving the muscle function of a mammal, comprising administering a nutritional composition comprising at least 18 en% of proteinaceous matter having a leucine content of at least 9.5 wt% based on total proteinaceous matter, a lipid fraction comprising at least one ⁇ -3-polyunsaturated fatty acid selected from the group of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), eicosatetraenoic acid (ETA) and docosapentaenoic acid (DPA).
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • ETA eicosatetraenoic acid
  • DPA docosapentaenoic acid
  • compositions of the invention may be administered under the supervision of a medical specialist, or may be self-administered.
  • composition may be administered enterally or orally.
  • the mammal preferably is a human.
  • the invention further relates to the following items:
  • mice Male CD2F1 mice at 6-7 weeks of age, (BALB/c x DBA/2, Harlan / Charles River the Netherlands) were individually housed in a climate-controlled room (12:12 dark-light cycle with a constant room temperature of 21 ⁇ 1 °C). After acclimatization for one week mice were divided into weight-matched groups: (1) control receiving control chow, (2) tumor-bearing receiving control chow, and (3) tumor-bearing receiving experimental diets. Data shown are derived from the combination of several experimental runs with identical animal characteristics and experimental procedures (unless stated otherwise) and differ only in the experimental diets used. All experimental procedures were approved by the Animal Ethical Committee (DEC consult, Bilthoven, The Netherlands) and complied with the principles of good laboratory animal care.
  • the AIN93-M control diet in the category A experiments contained per kg feed: 126 g protein (100 % casein), 727 g carbohydrates and 40 g fat (100 % soy oil) (Research Diet Services, Wijk bij Duurstede, the Netherlands).
  • Experimental diets in this category were adjusted to control diets by partly replacing the carbohydrates and/or soy oil by protein and leucine (151 g casein/kg and 16 g leucine/kg feed; TB+hpr+leu), high protein and fish oil (151 g casein/kg and 22 g fish oil/kg feed; TB+hpr+fo), or high protein and leucine and fish oil (151 g casein/kg, 15 g leucine/kg and 22 g fish oil/kg food; TB+hpr+leu+fo).
  • the 22 g fish oil contained 6.9 g EPA and 3.1 g DHA resulting in a ratio of 2.2:1.
  • the control diet was iso-caloric and iso-nitrogenous to the control diet in the A-category of experiments and contained per kg feed 126 g protein (casein), 53 g fat (corn oil), and 699 g carbohydrates.
  • the iso-caloric experimental diet (further referred to as Specific Nutritional Composition; SNC) contained per kg feed: 210 g protein (189 g intact protein of which 68 % casein and 32 % whey and 21 g free leucine), 53 g fat (20.1 g corn oil, 10.2 g canola oil, and 22.2 g fish oil), 561 g carbohydrates, 18 g galacto-oligosaccharides and 2 g fructo-oligosaccharides.
  • SNC Specific Nutritional Composition
  • Murine C-26 adenocarcinoma cells were cultured in vitro with RPMI 1640 supplemented with 5% fetal calf serum and 1% penicillin-streptomycin. Tumor cells were trypsinized in a sub-confluent state and, after washing, suspended in Hanks' balanced salt solution (HBSS) at a concentration of 2.5 x 10 6 cells mL -1 . Under general anesthesia (isoflurane/N 2 O/O 2 ), tumor cells (5 x 10 5 cells in 0.2 mL) were inoculated subcutaneously into the right inguinal flank of the mice. Control (C) animals received a sham injection with 0.2 mL HBSS.
  • HBSS Hanks' balanced salt solution
  • mice were anaesthetized and weighted at day 20 after tumor inoculation.
  • Skeletal muscles e.g. m. Tibialis Anterior (mTA), m. Gastrocnemius (mG), m. Extensor Digitorum Longus (mEDL) and M. Soleus (mS)
  • the tumor, spleen, kidneys, liver, epididymal fat, thymus, lungs and heart were dissected and weighed.
  • Carcass mass was calculated by subtracting tumor mass from body mass.
  • muscle function was tested ex vivo in the category B experiment.
  • force-frequency characteristics (10 to 167 Hz, 250 ms) were determined and after replenishing the organ buffer and a resting period of 5 min, muscles were subjected to an exercise protocol (83 Hz, 250 ms every 1000 ms). This protocol represents a moderate load, comparable with normal daily activity. At the frequency used, complete tetanus of the muscle is reached. Isometric force signals of the force-frequency curve were analyzed for maximal and total force and for maximal contraction and relaxation velocity.
  • Body and carcass weight were significantly lower in tumor-bearing mice (TB-CON) compared to control mice (CON) on day 20 ( Table 2A ).
  • the difference in body weight change already being significant at day 15 after tumor inoculation (Table 2C ).
  • a significant lower fat mass (epididymal fat) and muscle mass was observed in the TB-CON mice ( Table 2B ).
  • Food intake was not different between groups ( Table 2D ).
  • the tumor-bearing mice receiving the Specific Nutritional Combination (TB-SNC group) had a higher body weight, and delta body weight compared to TB-CON mice.
  • BW body weight
  • delta BW BW day 20 minus BW day
  • delta CW CW day 20 minus CW day
  • TW tumor weight
  • mTA muscle Tibialis Anterior
  • mG muscle Gastrocnemius
  • mEDL muscle Extensor Digitorum Longus
  • mS muscle Soleus.
  • CT90 was significantly different between TB-SNC and TB-CON at lower frequencies at which total tetanus could be obtained (83 and 100 Hz). These data suggest that at frequencies (83-100 Hz) relevant for efficient physical performance (tetanus present), besides muscle mass-dependent changes, also muscle mass-independent changes had occurred that were corrected by specific nutritional intervention. Therefore, an exercise protocol of 100 repeated pulses was applied at 83 Hz. Again, CON and TB-SNC were significantly different from TB-CON during the whole exercise protocol for maximal contraction force ( Figure 3A ) and maximal contraction velocity ( Figure 3C ). When maximal contraction force was corrected for muscle mass ( Figure 3B ) curve positions remained, with only significant differences between CON and TB-CON. Maximal contraction velocity of the TB-SNC group, however, was still significantly different from TB-CON when corrected for muscle mass in the first repeats of the exercise ( ⁇ 10 repeats) ( Figure 3D ).
  • TB-CON mice were significantly less active than controls on days 16-17 and 18-19 (P ⁇ 0.01), resulting in a drastic decrease in overall activity in the TB-CON mice.
  • the TB-SNC mice were less active than control mice during the dark on day 18-19 (P ⁇ 0.05), but more active than TB-CON mice on those days (P ⁇ 0.05).
  • BCAA supplementation In healthy individuals this signal is likely to be short-lived due to the 'muscle-full phenomenon' induced by normal nutritional intake and homeostatic control mechanisms. In contrast, long lasting effects of BCAA supplementation were reported in patients with a metabolic or nutritional deficiency like in septic or cancer patients. In these patient groups BCAA supplementation was reported to result in positive effects on albumin status, quality of life and overall survival. Moreover, it has been reported that protein synthesis can only be stimulated in the presence of a high supply of balanced amounts of essential amino acids ( Rooyackers, O. E. and Nair, K. S. Annu Rev Nutr., 17: 457-485., 1997 ).
  • Organ (wet) mass of kidney, liver, intestine, thymus and heart were unaffected or decreased with increased cachexia.
  • Nutritional supplementation resulting in increased carcass weight had no effect or partly normalized the loss in organ mass.
  • none of the selected ingredients increased tumor size.
  • the complete nutritional combination showed a reduction in tumor size in experiment B.
  • Chevalier et al. reported that patients with advanced colorectal cancer showed less contrast between day time and night time activity (nocturnal sleep) ( Chevalier, V., Whilet, M. C., Cure, H., and Chollet, P. Oncol Rep, 10: 733-737, 2003 .). Individual activity patterns have even been suggested to be predictive of the patients' survival, tumor response and quality of life. The possibility of a tumor-induced disturbance in diurnal activity patterns is supported by our data, indicating a tumor-related shift in activity from the dark to the light period. The specific nutritional combination tested shows a clear trend to reduce this effect. Normal sleep patterns are critically dependent on the circadian release of melatonin from the pineal gland.
  • DHA-enriched formulas have been reported to normalize melatonin secretion in ( ⁇ -3)-deficient rats ( Zaouali-Ajina, M., Gharib, A., Durand, G., Gazzah, N., Claustrat, B., Gharib, C., and Sarda, N. J Nutr, 129: 2074-2080, 1999 .) ; this might also be an explanation for the results obtained in our experiments.
  • a sip feed may in particular comprise macronutrients in ranges specified in Table 3.
  • macronutrients such as minerals, vitamins, etc.
  • one or more other food-grade additives e.g. flavourings; preservatives; non-proteinogenic amino acids, such as carnitine
  • Table 3 Nutritional composition of a Sip Feed (per 100 ml) Proteinaceous matter (equivalent) (g) 9 - 12 - containing total whey protein 1 - 9 - containing total leucine (g) 1.5 - 2.5 - of which Leucine as free amino acid (g) 0.9 - 1.5 Carbohydrate (g) 10 - 25 Fat (g) 2 - 6 - of which unsaturated 2 - 6 - of which omega 3 poly unsaturated 0.8 - 2 - of which EPA,DHA, ETA, DPA 0.2 - 2 Soluble fibre, dietary g 1 - 4
  • Table 4 Nutritional composition of a sip feed (per 100 ml) Proteinaceous matter (equivalent) (g) 10.1 - containing total whey protein 2.9 - containing total leucine (g) 2.0 - of which Leucine as free amino acid (g) 1.1 Carbohydrate (g) 17.4 Fat (g) 5.3 - of which unsatur
  • a tube feed may in particular comprise macronutrients in ranges specified in Table 5.
  • macronutrients such as minerals, vitamins, etc .
  • one or more other food-grade additives e.g . flavourings, preservatives
  • Table 5 Nutritional composition of a tube feed Proteinaceous matter (equivalent) (g) 6 - 10 - containing total whey protein 1 - 8 - containing total leucine (g) 1 - 2 - of which Leucine as free amino acid (g) 0.4 - 0.9 Carbohydrate (g) 10 - 25 Fat (g) 2 - 6 - of which unsaturated 2 - 6 - of which omega 3 poly unsaturated 0.4 - 1 - of which EPA,DHA, ETA, DPA 0.1 - 1 Soluble fibre, dietary g 1 - 4
  • Table 6 Nutritional composition of a tube feed Proteinaceous matter (equivalent) (g) 7.8 - containing total whey protein 2.9 - containing total leucine (g) 1.5 - of which Leucine as free amino acid (g) 0.8 Carbohydrate (g) 17.2 Fat (g) 5.4 - of which unsaturated 4.5 - of which omega 3 poly unsaturated 0.8
  • Table 7 The following composition (Table 7) was made according to standard procedures and is suitable for use according to the invention, preferably as a sip feed.
  • EXAMPLE 3 Muscle protein synthesis after nutritional supplementation in colorectal cancer patients.
  • a sip feed containing a specific nutritional combination as described in Table 4 from the possible compositions was tested on its capacity to influence muscle protein synthesis rate and compared to a control product as described in Table 8.
  • Table 8. Supplements Composition Specific Nutritional Combination (SNC) (100 ML) CONTROL (100 ML) Energy Kcal 160 Energy Kcal 160 Protein* g 10.1g Protein* g 6.0 Fat g 5.3 Fat g 5.8 Carbohydrates g 17.4 Carbohydrates g 21.0 * SNC: 2.9 g whey protein, 1.1g free leucine, balance casein; control only casein
  • Subjects were enrolled based on the inclusion/exclusion criteria described below. All subjects were able to walk, sit down and stand up on their own. Screening procedures not already performed in the context of their care for cancer was done prior to the study. A total of 24 subjects (12 each group) completed the protocol.
  • the inclusion criteria were as follows: (1) Radiographic evidence of cancer, (2) Age > 40 years (both male and female), (3) Ability to sign informed consent.
  • SNC specific nutritional combination according to the invention
  • Glucose concentrations were reduced in patients receiving the composition according to the invention (SNC) when compared to patients receiving the control supplement ( Figure 6 ). This is advantageous because low post prandial glucose levels can (on term) result in improved sensitivity of the muscle for an anabolic triggers (insulin).
  • the glycemic index (GI) of a carbohydrate provides a measure of its ability to raise postprandial glucose concentrations. High GI foods give higher postprandial blood glucose levels than those with a low GI. The GI of a carbohydrate also predicts the insulin response to that food.
  • the GI of a carbohydrate is calculated by assessing a 25g two-hourglycaemic response with that of a subsequent 25g carbohydrate standard glucose:
  • Glycaemic Index Methodology Available carbohydrate is defined for GI testing purposes as: Total carbohydrate minus the indigestible carbohydrates (soluble and insoluble) that are from a physiological point dietary fibres (e.g . inulin, FOS, type 3 resistant starch).
  • the samples provided should be representative of the product as available to the consumer in the market place.
  • All foods submitted for testing are tested in vivo, that is, in 10 human subjects consuming amounts containing the equivalent of 25g available carbohydrate.. They are healthy subjects with no chronic diseases, diabetes or glucose impairment. Subjects have a BMI between 18.5-27kg/m 2 .
  • Reference food The reference food is 25g glucose powder dissolved in 250mls water. Each person tests the reference food at least twice.
  • Test foods The test foods are prepared according to manufacturer's instructions, representing the food as normally consumed. The test foods are consumed once only on separate occasions as a portion providing 25g of available carbohydrate, defined as above.
  • Protocol Subjects Subjects are tested in the morning after a 10-12h overnight fast. Two fasting blood samples are taken (-5 & 0) 5 minutes apart after which subjects consume the test meal or reference food at an even rate over 15 minutes. Further blood samples are taken at 15, 30, 45, 60, 90 and 120 minutes after the beginning of the meal. The test meal and reference food should be consumed with a 250mls drink of water. This remains constant for each of the tests in the series.
  • Blood sampling Blood will be obtained by finger pricking.
  • Blood is collected without clotting inhibitors (heparin, EDTA).
  • Glucose assay Whole capillary blood or is measured by an automatic glucose analyzer. In this case, Hemocue glucose analysers are used.
  • Ax the AUC for the xth time interval (ie. between tx-1 and tx).
  • the other time intervals ie.
  • the GI value is the iAUC for each food expressed as a percentage of the mean iAUC of the two reference foods (glucose).
  • the GI of the test food is the mean GI ⁇ SEM of the 10 subjects.
  • Up to two outliers (an outlier is an individual whose GI differs from the mean by more than two SD) may be excluded from the data set. SEM should be within 20% of the mean.
  • Clinical trial setting 1 healthy volunteers.
  • the GI for the standard sip was 67 ⁇ 10 whereas the GI for the test drink was 40 ⁇ 4. Therefore the GI of Forticare was classified as low ( ⁇ 55) and the standard sip as medium (55-70).
  • Example 3 Glucose concentrations were reduced in patients receiving the specific nutritional combination SNC when compared to patients receiving the control supplement (Example 3, Figure 5 ).

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